The NOD mouse has been studied as a model for insulin dependent diabetes mellitus (IDDM). A major focus of research in this model has been the investigation of immunologic mechanisms to suppress the disease process. Oral tolerance is a classic mechanism for the induction of antigen specific peripheral immunologic tolerance, and we have been studying the suppression of experimental autoimmune diseases in a number of animal models, with a primary focus on experimental autoimmune encephalomyelitis (EAE). The oral administration of myelin basic protein (MBP) suppresses clinical and histologic manifestations of EAE and leads to the generation of CD8+ T cells that adoptively transfer protection and suppress in vitro antigen specific responses. The CD8+ T cells mediate their effect by the secretion of TGFbeta after being triggered by specific antigen. In the NOD mouse, we have found that oral tolerization to insulin delays the onset and reduces the incidence of diabetes over a one year period in animals administered 1 mg of porcine insulin orally twice a week for 5 weeks and then weekly until one year of age. As expected, orally administered insulin had no metabolic effect on blood glucose levels. The severity of lymphocytic infiltration of pancreatic islets was also reduced by oral tolerization to insulin. Furthermore, spleen cells from orally tolerized animals adoptively transfer protection against diabetes demonstrating that active cellular mechanisms are generated by oral insulin administration which suppress disease. These results raise the possibility that immunity to insulin may play a pathogenic role in diabetes in the NOD mouse and that oral tolerization to insulin may provide a new approach for the treatment of autoimmune diabetes. The present grant proposal will investigate basic mechanisms involved in suppression of diabetes by oral tolerization to insulin. The specific aims of the proposal are as follows: 1) Which portions of the insulin molecule trigger suppression of diabetes via oral tolerization? 2) Can protection of NOD mice from diabetes be enhanced by alternate dosing schedules or the use of adjuvants? 3) What are the characteristics of the cells generated which mediate suppression? 4) What are the in vivo mechanisms associated with disease suppression? 5) Does oral administration of other pancreatic antigens suppress diabetes?